Elton John is among countless patients worldwide who are counting on antibiotics to treat illness. His doctors hope a combination of antibiotics and surgery will correct an inflamed appendix that forced the musician to cancel his summer concert dates earlier this month.

Complicating matters for those on antibiotics is the growing resistance of bugs to the drugs, and the resulting scarcity of new and effective antimicrobial treatments. A year ago this month, Washington sought to start addressing the problem by folding into the wide-ranging FDA Safety and Innovation Act (FDASIA) law incentives designed to stoke commercial development of new antibiotics against superbugs and other viruses, and known by its earlier name of the Generating Antibiotic Incentives Now (GAIN) Act.

Most notably, the law created the “qualified infectious disease product” (QIDP) designation for antibiotic drug candidates, which entitles their developers to faster FDA reviews and five additional years of market exclusivity.

Turns out the GAIN anticipated by FDASIA is a small piece in a tapestry of new rules, incentives, and initiatives that officials, researchers, and physicians now say is needed to stimulate the number and types of new antibiotics needed against antimicrobial resistance.

The latest federal effort on antibiotics took place earlier this month, when FDA issued draft guidance intended to articulate its thinking on streamlining antibiotic development programs and clinical trial designs, even for non-QIDP drugs. Drugs that would be considered for streamlined development, according to FDA, include antibacterials for “serious” bacterial infections in patients with unmet medical need—including pathogen-focused antibacterials, even if they treat a single genus and species of bacteria. Conditions deemed “serious” are those associated with morbidity that has substantial impact on day-to-day function.

Because such patients have few or no other options, the agency wrote, “they are likely to be drugs that: 1) act via new mechanisms of action; 2) have an added inhibitor that neutralizes a mechanism of resistance; or 3) have an alteration in the structure of the molecule that makes the drug no longer susceptible to the mechanism of resistance to existing drugs.”

Antibacterial drugs for patients with intolerance or allergy to current drugs are deemed to address unmet medical needs—as opposed to drugs with slightly greater potency, for which FDA recommends traditional development programs.

Smaller Trials

In clinical trials, according to the draft guidance, an investigational drug can show superiority through comparison to the best-available active-control therapy where a best-available therapy may be suboptimal. Such trials can be conducted at “enriched” trial sites such as those with a high frequency of infections caused by bacterial pathogens associated with unmet medical need.

Trials designed to show substantial superiority need not be as large as traditional Phase III studies: About 97 patients per arm would be deemed adequate for studies where an investigational drug group is expected to show at least 85% percent success, compared with 65% for an active-control group.

The agency suggested that companies and other stakeholders submit comments on the draft guidance by September 30. As of July 15, no comments had been submitted electronically. Among groups studying the draft guidance is the Infectious Disease Society of America (IDSA). While it is crafting detailed comments, the coalition of physicians and researchers says that, in general, it likes what it sees.

“We’re very heartened that FDA is trying to move forward in encouraging more antibiotic development, specifically for the more serious and life-threatening infections, where there is tremendous unmet medical need,” Amanda Jezek, vp of public policy and government relations for IDSA, told GEN.

Particularly promising, she said, is the allowance for smaller clinical trials: “We think that that can be very helpful in terms of getting drugs out to patients who are most in need more quickly than they have been able to do in the past. We think that’s really promising.”

FDA’s guidance bears similarities to the “limited population antibacterial drug” (LPAD) approval pathway IDSA proposed last year, though the group is still seeking to see that pathway be written into law, and working with several members of Congress to develop such a bill. The LPAD pathway is one of several measures from Washington sought by the group. In 2010, it called for developing 10 new systemic antibiotics by 2020. Only one has been developed as of April, according to a follow-up report.

Reaching for a STAAR

Many of the measures sought by IDSA have been included in the proposed Strategies to Address Antimicrobial Resistance (STAAR) Act, a bill reintroduced last month by U.S. Rep. Jim Matheson (D-UT). STAAR calls in part for Washington to coordinate actions against antimicrobial resistance within a new Antimicrobial Resistance Office to be based within the Department of Health and Human Services. That’s a diplomatic way of acknowledging that the key agencies involved all fall under HHS—not only FDA, but CDC and NIH as well.

Within CDC, the STAAR Act would authorize the Antimicrobial Resistance Surveillance and Laboratory Network, and efforts to enhance the national capacity to prevent the transmission of resistant infections and the development of resistance. CDC published findings in March showing the CRE bacteria family has grown increasingly resistant to last-resort antibiotics during the past decade.

Within NIH, the bill would reauthorize the Antimicrobial Resistance Task Force, while establishing a new advisory board of outside experts; create an antimicrobial resistance strategic research plan; and authorize the new Clinical Trials Network on Antibacterial Resistance. Last month, NIH’s National Institute of Allergy and Infectious Diseases awarded $2 million to Duke University to establish the network, funding for which could reach $62 million by 2019, the agency has said.

“We think that’s a really important initiative and we’re excited that it’s going forward,” IDSA’s Jezek said. “We continue to make the point to NAID about how important this issue is, and we continue to advocate to them that they devote more resources to it.”

STAAR calls for expanding data collection efforts on antimicrobial resistance and for using that data, as well as developing and testing quality measures on antimicrobial use.

“My bill takes a common sense approach aimed at better understanding and monitoring the cause and spread of antimicrobial resistant infections, improving antibiotic development, and ultimately helping people who need and rely on antibiotics,” Rep. Matheson said in a statement.

While Congress typically split along party lines on such issues, members of both parties put principle before politics last year when they crafted FDASIA, and then passed it by bipartisan margins in the Senate (a 92–4 vote), plus a voice vote in the House of Representatives. Similar outreach to officials by industry and researchers will be needed for STAAR, which failed to become law in 2007 and 2009. Lawmakers and advocates should consider more comprehensive antibiotics legislation that adds IDSA’s LPAD pathway to STAAR—and which will need a Republican champion, especially in the GOP-run House.

Adding to the nation’s array of antibacterial programs will require addressing two challenges. One is cost, given the tight budgets likely to prevail even if both parties ever agree to spending plans for FY 2013 and 2014. The other challenge is demonstrating effectiveness, as with the drug candidates envisioned by STAAR and FDA’s draft guidance. Washington will need to show that the new measures will fuel development of the number and variety of antibacterial drugs needed as the current generation exhausts its effectiveness against bacteria and other organisms.

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